| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| SYSTEMIC LUPUS ERYTHEMATOSUS, NOS |
|
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective for this study will be to assess the proportion of subjects with a new clinical flare of SLE (BILAG “A” or “B”) during the 1 year double-blind treatment period, comparing abatacept with placebo on a background of tapering glucocorticosteroids. |
|
| E.2.2 | Secondary objectives of the trial |
1) Assess the proportion of subjects with a new clinical flare of SLE (BILAG “A” or
“B” within the initial 6 months of the double-blind trt period.
2) Evaluate the proportion of subjects who during the study experienced a BILAG “A”
or “B”) flare and/or had an increase in prednisone or prednisone equivalent dosage for clinical re-activation of SLE that did not meet BILAG “A” or “B” criteria for flare of SLE.
3) Assess total number of BILAG “A” and BILAG “B” flares and evaluate the time to occurrence of a new clinical flare of SLE in the two trt groups.
4) Assess proportion of subjects in each study arm who have no flares of their lupus for at least 6 consecutive months.
5) Assess SLICC/ACR Damage Index at one year compared with baseline for the two
trt groups.
6) Assess total exposure to glucocorticosteroids in the two groups, as measured by total prednisone or prednisone equivalent“area under the curve” (AUC).
7) Assess average glucocorticosteroid dose at flare.
|
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1) Subjects must have SLE as defined by meeting 4 of the 11 classification criteria of
the American College of Rheumatology for the classification of Systemic Lupus
Erythematosus (Appendix 1), either sequentially or coincident. The 4 criteria need not
be present at study entry, but have occurred at some time during the course of the
disease.
2) Within 14 days of the screening visit, subjects must have at least one of the following flare manifestations of SLE, as defined by the BILAG criteria as modified for use in this study.
The flare manifestation may represent the initial activity within that organ system or may be a recurrence of activity in an organ system previously affected. If the latter is the case,
the organ system now flaring must have been inactive for at least 3 months prior to
the onset of the current flare. (the subject may be experiencing other BILAG “A”
or “B” features of lupus as well (other than renal or central nervous system
which are specifically excluded from entry), but features other than those
specified below are not sufficient for entry into the study):
a) Active mucocutaneous discoid lesions:
i) “A”: severe active facial and/or extensive discoid lesions (> 2/9 of body
surface area), scarring or causing disability recorded as >1.
ii) “B”: localized active discoid lesions (< 1/9 total body surface area), including
lupus profundus recorded as >1.
The skin lesions must be actively inflamed; they cannot be solely chronic
changes, e.g. scar with depigmentation. In order to satisfy inclusion rules, the
currently active lesions cannot represent ongoing chronic and continuous
activity - they must constitute a flare, either newly inflamed or previously
inflamed but quiescent for at least 3 months.
b) Active polyarthritis:
i) “A”: severe polyarthritis recorded as >1 with loss of function (not responsive to steroids less than 10 mg per day, antimalarials, NSAIDs)
ii) “B”: Arthritis recorded as >1: active joint inflammation without loss of functional range of motion.
At least 3 actively inflamed joints--swollen, tender, erythematous--not
isolated Jaccoud arthropathy although the presence of Jaccoud arthropathy in
a subject with active inflammation will not preclude study entry. The
inflamed joints cannot have been chronically and continuously inflamed- they
must constitute a flare, either newly inflamed or previously inflamed but
quiescent for at least 3 months.
c) Active serositis (pleuritis/pericarditis):
i) “A”: Symptomatic effusion recorded as >1 plus two other criteria listed below >1 or four of the following criteria listed below each recorded as >1: pleuropericardial pain; dyspnea; friction rub; chest x-ray revealing pleural or pericardial effusion; electrocardiogramchanges of pericarditis; or cardiac arrhythmia including tachycardia > 100
beats per minute in the absence of fever.
ii) “B”: Two of the following criteria listed below each recorded as >1: pleuropericardial pain; dyspnea; friction
rub; chest x-ray revealing pleural or pericardial effusion; electrocardiogram
changes of pericarditis; or cardiac arrhythmia including tachycardia > 100
beats per minute in the absence of fever.
Although commonly used in some practices, echocardiographic confirmation
of the presence of pericardial disease is not considered a BILAG criterion and
therefore cannot be substituted for any of the criteria noted above.
Eligibility of subjects for entry into the study is based on their current disease activity
(flare characteristics). The flare may represent:
i) new activity in an organ system that had been quiescent for at least 3 months
OR
ii) new worsening in an organ system that had been minimally or not active for at
least 3 months, but that had been active in the past (i.e. re-activation of
previously active organ system).
iii) Activity in an organ system that had not been involved previously.
4) Men and women (not nursing and not pregnant), at least 18 years of age. Men, and women of childbearing potential are eligible if they are practicing effective
contraceptive measures. |
|
| E.4 | Principal exclusion criteria |
1) Women who are pregnant or breast-feeding.
2) Women with a positive pregnancy test on enrollment or prior to study drug
administration.
3) WOCBP who are unwilling or unable to use an acceptable method to avoid
pregnancy for the entire study period and for up to 10 weeks after the last infusion of study medication.
4) Males unwilling or unable to use an adequate method of contraception for the entire study period and for up to 10 weeks after the last infusion of study medication.
5) Treatment of current SLE flare with corticosteroids (prednisone or prednisone-equivalent), for more than 10 days prior to randomization, or at any time with a dose ≥30 mg (prednisone or prednisone) equivalent per day.
6) Active anti-phospholipid antibody syndrome, (i.e. recent untreated thromboses,
cerebral or pulmonary emboli, pregnancy loss, pleurisy due to thromboembolic
phenomena) as the sole or primary feature of their SLE or SLE-like syndrome. Any
subject requiring anti-coagulation, other than low-dose aspirin, for anti-phospholipid
antibody syndrome will be excluded from this study.
7) Subjects with drug-induced SLE, rather than “idiopathic” SLE.
8) Subjects with other autoimmune disease as a main diagnosis other than SLE (e.g.;
RA, MS).
9) Current symptoms of severe, progressive, or uncontrolled renal, hepatic,
hematological, gastrointestinal, non-SLE pulmonary, non-SLE cardiac, neurological,
or cerebral disease; pulmonary and/or cardiac manifestations of SLE shall not
constitute an exclusion to study entry. Concomitant medical conditions that, in the
opinion of the Investigator, might place the subject at unacceptable risk for
participation in this study.
10) Concomitant illness that in the opinion of the investigator, is likely to require
additional glucocorticosteroid therapy during the study, (e.g.; asthma).
11) Female subjects with a breast cancer screening that is suspicious for malignancy and in whom the possibility of malignancy cannot be reasonably excluded following
additional clinical, laboratory or other diagnostic evaluations.
12) Subjects with a history of cancer within the last five years (other than non-melanoma
skin cell cancers cured by local resection). Existing non-melanoma skin cell cancers
must be removed prior to randomization (Day 1 treatment).
13) Subjects who have a history of clinically significant drug or alcohol abuse. Subjects currently taking methotrexate who admit to consumption of more than an average of 1 alcoholic drink per day.
14) Subjects with any serious bacterial infection (such as pneumonia, renal infection and sinusitis), unless treated and resolved with antibiotics or chronic bacterial infection (such as pyelonephritis, osteomyelitis and lung infection with bronchiectasis) in the previous 3 months.
15) Subjects with active tuberculosis (TB) requiring treatment within the previous
3 years. Subjects with a positive PPD at screening will not be eligible for the study
unless they have a negative chest x-ray at enrollment and have completed treatment
for latent TB. A PPD response that is equal to or greater than 10 mm should be
considered a positive test, although more conservative criteria may be applied as
determined by the clinical circumstance and investigator according to published
guidelines and/or local standards endorsed by the medical society.
16) Subjects with herpes zoster that resolved less than 2 months prior to enrollment.
17) Subjects with evidence (as assessed by the Investigator) of active or latent bacterial or viral infections at the time of potential enrollment, including subjects with evidence of Human Immunodeficiency Virus (HIV) infection.
18) Subjects currently on hydroxychloroquine or chloroquine with evidence of
retinopathy within 6 months of enrollment or who have had no ophthalmologic
evaluation and will not have this examination done.
19) Subjects who have at any time received treatment with CTLA4Ig or abatacept.
20) Subjects who have received treatment with any investigational drug within 28 days(or less than 5 terminal half lives of elimination) of the Day 1 dose
21) Subjects who have at any time received treatment with rituximab.
22) Subjects who have received treatment with cyclophosphamide within the 1 year priorto enrollment. Any such subject with hematuria, regardless of the time since the last cyclophosphamide dose will be excluded from this study.
23) Subjects who have received treatment with cyclosporine, another calcineurin inhibitor or other immunosuppressive medication (oral or topical) within 3 months of enrollment.
24) Subjects who have received treatment with gamma globulin within 4 months of
enrollment.
See protocol for additional exclusion criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy measure is the occurrence of SLE disease flare during the 12 month treatment period. The occurrence of flare will be summarized as the proportion of subjects in each of the two treatment arms to experience one or more flares. The treatment difference will be provided along with its 95% confidence interval. In addition, the hazard ratio and its 95% confidence interval, adjusted for the randomization strata using Cochran-Mantel-Haenszel (CMH) methods, will be summarized. Subjects whose active manifestations of lupus at study entry do not remit within 8 weeks of randomization will also be counted as having experienced a lupus flare. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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